tbuckley/cabot-search huggingface dataset:
Ibrutinib and venetoclax as primary therapy in symptomatic, treatment-naïve Waldenström macroglobulinemia
Authors: Jorge J. Castillo, Andrew R. Branagan, David Sermer, Catherine A. Flynn, Kirsten Meid, Megan Little, Katherine Stockman, Timothy White, Alexa Canning, Maria L. Guerrera, Amanda Kofides, Shirong Liu, Xia Liu, Kris Richardson, Nicholas Tsakmaklis, Christopher J. Patterson, Zachary R. Hunter, Steven P. Treon, Shayna Sarosiek
Journal: Blood (2023)

Abstract Concurrent Bruton tyrosine kinase and BCL2 inhibition has not yet been investigated in Waldenström macroglobulinemia (WM). We performed an investigator-initiated trial of ibrutinib and venetoclax in symptomatic treatment-naïve patients with MYD88-mutated WM. Patients received ibrutinib 420 mg once daily (cycle 1), followed by a ramp-up of venetoclax to 400 mg daily (cycle 2). The combination was then administered for 22 additional 4-week cycles. The attainment of very good partial response (VGPR) was the primary end point. Forty-five patients were enrolled in this study. The median baseline characteristics were as follows: age 67 years, serum IgM 43 g/L, and hemoglobin 102 g/L. Seventeen patients (38%) carried CXCR4 mutations. Nineteen patients (42%) achieved VGPR. Grade 3 or higher adverse events included neutropenia (38%), mucositis (9%), and tumor lysis syndrome (7%). Atrial fibrillation occurred in 3 (9%), and ventricular arrhythmia in 4 (9%) patients that included 2 grade 5 events. With a median follow-up of 24.4 months, the 24-month progression-free survival (PFS) and overall survival (OS) rates were 76% and 96%, respectively, and were not impacted by CXCR4 mutations. The median time on therapy was 10.2 months, and the median time after the end of therapy (EOT) was 13.3 months. Eleven of the 12 progression events occurred after EOT, and the 12-month PFS rates after EOT were 79%; 93% if VGPR was attained, and 69% for other patients (P = .12). Ibrutinib and venetoclax induced high VGPR rates and durable responses after EOT, although they were associated with a higher-than-expected rate of ventricular arrhythmia in patients with WM, leading to early study treatment termination. This trial was registered at www.clinicaltrials.gov as #NCT04273139.
Neurodevelopmental Programming of Adiposity: Contributions to Obesity Risk
Authors: Alicja A Skowronski, Rudolph L Leibel, Charles A LeDuc
Journal: Endocrine Reviews (2023)

This review analyzes the published evidence regarding maternal factors that influence the developmental programming of long-term adiposity in humans and animals via the central nervous system (CNS). We describe the physiological outcomes of perinatal underfeeding and overfeeding and explore potential mechanisms that may mediate the impact of such exposures on the development of feeding circuits within the CNS-including the influences of metabolic hormones and epigenetic changes. The perinatal environment, reflective of maternal nutritional status, contributes to the programming of offspring adiposity. The in utero and early postnatal periods represent critically sensitive developmental windows during which the hormonal and metabolic milieu affects the maturation of the hypothalamus. Maternal hyperglycemia is associated with increased transfer of glucose to the fetus driving fetal hyperinsulinemia. Elevated fetal insulin causes increased adiposity and consequently higher fetal circulating leptin concentration. Mechanistic studies in animal models indicate important roles of leptin and insulin in central and peripheral programming of adiposity, and suggest that optimal concentrations of these hormones are critical during early life. Additionally, the environmental milieu during development may be conveyed to progeny through epigenetic marks and these can potentially be vertically transmitted to subsequent generations. Thus, nutritional and metabolic/endocrine signals during perinatal development can have lifelong (and possibly multigenerational) impacts on offspring body weight regulation.
Pueraria lobata-derived exosome-like nanovesicles alleviate osteoporosis by enhacning autophagy
Authors: Weiqiang Zhan, Mingzhu Deng, Xinqia Huang, Dong Xie, Xiang Gao, Jiaxian Chen, Zhen Shi, Jiaxu Lu, Hao Lin, Peng Li
Journal: Journal of Controlled Release (2023)

Osteoporosis (OP) is the most common bone disorder worldwide, especially in postmenopausal women. However, many OP drugs are not suitable for long term use due to major adverse effects. Therefore, there is an urgent need to identify more effective and safe therapeutic drugs. Pueraria lobata has been reported to promote osteoblast growth in bone regeneration, but the exact mechanisms still need further exploration. The current study found that Pueraria lobata-derived exosome-like nanovesicles (PELNs) promoting primary human bone mesenchymal stem cells (hBMSCs) differentiation and mineralization both in vitro and in ovariectomized (OVX)-induced osteoporotic rats. Interestingly, the relative abundance of harmful strains significantly decreased in the intestine of the osteoporosis SD rat model administrated PELNs via the regulation of trimethylamine-N-oxide (TMAO), a metabolite of gut microbiota. Moreover, RNA sequencing revealed that the osteogenic activity of PELNs is revealed to autophagy signaling. In vitro and in vivo experiments also showed that the treatment with PELNs promoted the differentiation and function of hBMSCs by elevating autophagy via the degradation of TMAO. Collectively, PELNs demonstrate promise as a therapeutic approach for OP, with TMAO emerging as a potential target of OP treatment.
DEBATE UPFRONT vs DELAYED TRANSPLANT
Authors: F. Gay
Journal: HemaSphere (2023)

Standard treatment approach for newly diagnosed patients eligible for high-dose chemotherapy consists of a multiagent induction treatment (including, based on local availability and approval, anti CD38 Monoclonal antibody, proteasome inhibitor, immunomodulatory agent and dexamethasone) followed by stem cell collection and then high dose chemotherapy (Melphalan 200 mg/sqm, Mel200) and autologous stem cell transplantation (ASCT). Several trials consistently showed a progression free survival benefit for Mel200-ASCT upfront vs novel agent based chemotherapy, including bortezomib-lenalidomide-dexamethasone and carfilzomib lenalidomide dexamethasone. Stem cell collections is now adequate in the majority of the patients, and rarely patients who are intended for ASCT have to be excluded from this therapeutic approach. With the current supportive measures, Mel200-ASCT became a well tolerated procedures, with a mortality rate <1% and manageable and predictable toxicities (mainly hematological, infections and gastrointestinal toxicities). In many countries, patients can be also managed in the outpatient setting. Despite improvement in progression free survival, no benefit in terms of OS has been proven so far in randomized studies were ASCT is compared with combinations of proteasome inhibitors and immunomodulatory agents. This might be related to the general improvement in survival for myeloma patients, and as a consequence a very long follow-up is needed to show OS benefit. Another reason could be that now, with improvement in supportive cares, many patients can indeed be able to receive ASCT at first relapse. Indeed, prolonged remission after first line, even with so far no improvement in OS, is of importance since outcome after first line is generally the longest in the patient journey, and a proportion of patients who relapse might not be able to get to second line therapy.
P27 HIGH DOSE CYCLOPHOSPHAMIDE AS MOBILIZATION REGIMEN IN NEWLY DIAGNOSED MULTIPLE MYELOMA: SAFETY AND EFFICACY IN AN OUTPATIENT SETTING. SINGLE CENTER EXPERIENCE
Authors: L. Massarotti, A. Branca, L. Pavan, A. Maroccia, C.A. Cavarretta, V. Ruocco, I. Zatta, G. Scapinello, F. Piazza, F. D’Amore, F. Lessi, C. Gurrieri, R. Zambello, L. Trentin, T. Berno
Journal: HemaSphere (2023)

Background and aim of the study: High-dose chemotherapy followed by autologous stem-cells transplantation (ASCT) is the standard treatment approach in eligible newly diagnosed multiple myeloma (MM) patients. The use of Daratumumab in frontline therapy seems to affect stem cell mobilization and engraftment with lower number of stem cells collected and delayed neutrophil engraftment respectively. A common standard protocol for hematopoietic stem and progenitor cells (HPSC) mobilization before ASCT in MM is currently not defined but the use of high dose cyclophosphamide (Cy) (3-4 gr/m2) seems associated with improved stem cell mobilization (SC) and collection with however an increase rates of severe neutropenia, infection and hospitalitazion. Moreover the administration of high dose of Cy, usually requires hospitalization to provide adequate hydration. The primary aim of this study is to assess the safety and efficacy of the mobilization therapy with low and high dose of Cy (2-3-4 g/m2) plus G-CSF in an outpatient setting. Materials and methods: From January 2022 to November 2022, 26 newly diagnosed multiple myeloma transplant eligible patients, 81% of them treated with daratumumab combination frontline, underwent mobilization with low (2 gr/m2; LD) and high dose (3-4 gr/m2; HD) Cy in outpatient setting. The LD-Cy was administered in one day while HD-Cy was split in two consecutive days (day +1 and +2). G-CSF (5 mcg/kg) was started at day +6. Use of plerixafor was permitted if circulating CD34+ cells were at least 5 uL at day +10. Eighty-five percent of patients received HD-Cy. Results: Chemotherapy was well tolerated. The most common adverse events (AEs) were hematological: grade 3-4 neutropenia (100%) and grade 3-4 thrombocytopenia (15%). The non hematological AEs of grade 3-4 were limited to one case of febrile neutropenia (G3) which required hospitalization. No treatment-related mortality was observed. 23% of patients reported non hematological mild AEs (G1-G2) including nausea, asthenia and constipation. The rate of AEs is independent of drug dosage. In our cohort no renal impairment neither worsening of renal function were observed. There was no statistically significant difference in median eGFR value before and after chemotherapy (at day +6). The median amount of SCs collected was 9.85×106/kg. The rate of mobilization failure (defined as failure to collect ≥2×106/kg) was 0%. One patient (3,8%) required use of Plerixafor. In 4 patients two consecutive apheresis sessions were required. Conclusion: Our results suggest that outpatient mobilization with low and high dose of cyclophosphamide is safe and may be considered for successful stem cell mobilization in MM transplant eligible patients treated with daratumumab frontline.
ANTIBODY DRUG CONJUGATES (ADCS)
Authors: E. Terpos
Journal: HemaSphere (2023)

BCMA (B-cell maturation antigen) is a and member of the tumor necrosis factor receptors superfamily, which is primarily expressed in late-stage B-lineage cells, normal and malignant plasma cells, and B-lymphocytes, with very low expression on nonhematologic cells. Belantamab Mafodotin (belamaf) is the first approved anti-BCMA ADC for the treatment of relapsed/refractory multiple myeloma (RRMM). This afucosylated, humanized, IgG1 monoclonal antibody is conjugated to monomethyl auristatin F, an inhibitor of tubulin polymerization, through a protease-resistant maleimidocaproyl linker. Following binding to the plasma cell surface, belamaf is internalized, and the active cytotoxic drug is released following enzymatic cleavage leading to cell death. Mechanisms of action include also NK-cell mediated ADCC and ADCP. DREAMM-2 trial explored the safety and activity of belamaf in MM patients who were refractory to PI, IMiD and an anti-CD38 mAb alone or in combination. Patients were randomized 1:1 to receive 2.5 mg/kg (n = 97) or 3.4 mg/kg (n = 99) belamaf, iv, every three weeks until disease progression or unacceptable toxicity. After a median follow up of 9 months, the median PFS was 2.8 and 3.9 months in the two cohorts, respectively, with one year OS probability of 53%. ORR was similar among the group of patients with 3–6 (34%) and seven or more (30%) prior lines of therapy. Two post hoc analyses demonstrate the efficacy of belamaf in the subgroups of patients with high-risk cytogenetics and impaired renal function (EGFR 30 ml/min). Regarding AEs, this study confirmed the frequent occurrence of corneal events; 72% of patients developed keratopathy of any grade, while 31% developed keratopathy grade 3–4. Keratopathy was attributed to the MMAF and was reversible after temporary discontinuation of the drug. Other frequent adverse events grade 3–4 were anemia (21%) and thrombocytopenia (22%). Based on this study belamaf was giver provisional approval by EMA for use in triple-class refractory RRMM at a dose of 2.5 mg/kg every 3 weeks. Currently, the role of belamaf is being evaluated in earlier RRMM settings. Three-phase III studies evaluate the safety and efficacy of belamaf in combination with pomalidomide (NCT04162210; DREAMM-3), daratumumab plus bortezomib (NCT04246047; DREAMM-7), or pomalidomide plus bortezomib (NCT04484623: DREAMM-8). The results are eagerly awaited. MEDI2228 is another antibody-drug conjugate (ADC) composed of fully human monoclonal antibody, conjugated to a dimeric cross-linking pyrrolobenzodiazepine dimer via a protease-cleavable dipeptide linker8/42. MEDI2228 has shown potent antitumor activity in preclinical models, including cell lines resistant to lenalidomide. Phase 1 data in heavily pretreated patients were encouraging.
HOW TO HARNESS NEW IMMUNOTHERAPIES WITH COMBINATION STRATEGIES?
Authors: H. Einsele
Journal: HemaSphere (2023)

Immunotherapy includes all treatment approaches that use components or mechanisms of the immune system to fight malignant cells. These therapeutic approaches include e.g. bispecific antibodies and CAR-T cell therapy. By adding immune checkpoints, anti-CD38 Abs, IMiDs, CelMODs and tyrosine kinase inhibitors their effectiveness can be increased. Preclinical data as well as data from clinical trials using this combination approach will be presented. Bispecific Antibodies Another approach to fighting cancer in the field of immunotherapy is bispecific antibodies, which were clinically developed at the University Hospital in Würzburg and are now called bispecific T cell engagers. These antibodies contain the binding parts of two different monoclonal antibodies and can thus recognize two different surface structures and bind them together. Accordingly, cancer cells can be bound to highly active T cells of the immune system via bispecific antibodies. This reprograms the immune cell and induces tumor cell killing. CAR T cell therapy In CAR T cell therapy functional autologous T cells are removed from the patient’s blood. These are genetically modified in such a way that they form a receptor on their cell surfaces that recognizes the cancer cells. These CAR-T cells are then multiplied and given to the patient following a lymphodepleting therapy to optimize CAR T cell expansion and activation. Once established in the body, CAR-T cells are able to kill cancer cells.
A preparation method for mRNA-LNPs with improved properties
Authors: Cong Geng, Kefan Zhou, Ying Yan, Chan Li, Beibei Ni, Jiangman Liu, Yeming Wang, Xiaoyan Zhang, Dazhuang Wang, Lu Lv, Yongchuan Zhou, Anhua Feng, Yajuan Wang, Chunlei Li
Journal: Journal of Controlled Release (2023)
Hepatocytes of mice and men: Different regenerative signals?
Authors: George K. Michalopoulos
Journal: Hepatology (2023)

Department of Pathology, University of Pittsburgh School of Medicine and UPMC 1Correspondence George K. Michalopoulos. Email: [email protected] ABBREVIATIONS: ECM, Extracellular Matrix; EGF, Epidermal Growth Factor; HGF, Hepatocyte Growth Factor; IL1β Interleukin 1 beta; Il6, Interleukin 6; MET, The HGF receptor; MMP, Matrix Metallopeptidase; NFκB, Nuclear Factor kappa B; PDGF, Platelet derived Growth Factor; PHx, 2/3 Partial Hepatectomy; TGFα, Transforming Growth Factor alpha; TGFβ, Transforming Growth Factor beta; TNFα, Tumor Necrosis Factor alpha
Benefit and harm of waiting time in liver transplantation for HCC
Authors: Pam Elisabeth van der Meeren, Roeland Frederik de Wilde, Dave Sprengers, Jan Nicolaas Maria IJzermans
Journal: Hepatology (2023)

Liver transplantation is the most successful treatment for limited-stage HCC. The waiting time for liver transplantation (LT) can be a critical factor affecting the oncological prognosis and outcome of patients with HCC. Efficient strategies to optimize waiting time are essential to maximize the benefits of LT and to reduce the harm of delay in transplantation. The ever-increasing demand for donor livers emphasizes the need to improve the organization of the waiting list for transplantation and to optimize organ availability for patients with and without HCC. Current progress in innovations to expand the donor pool includes the implementation of living donor LT and the use of grafts from extended donors. By expanding selection criteria, an increased number of patients are eligible for transplantation, which necessitates criteria to prevent futile transplantations. Thus, the selection criteria for LT have evolved to include not only tumor characteristics but biomarkers as well. Enhancing our understanding of HCC tumor biology through the analysis of subtypes and molecular genetics holds significant promise in advancing the personalized approach for patients. In this review, the effect of waiting time duration on outcome in patients with HCC enlisted for LT is discussed.
Single-cell dissection of the multicellular ecosystem and molecular features underlying microvascular invasion in HCC
Authors: Ke Li, Rui Zhang, Fukai Wen, Yunzheng Zhao, Fanshuai Meng, Qingyu Li, Aimin Hao, Bailu Yang, Zhaoyang Lu, Yifeng Cui, Meng Zhou
Journal: Hepatology (2023)

Background and Aims: Microvascular invasion (MVI) is a crucial pathological hallmark of HCC that is closely associated with poor outcomes, early recurrence, and intrahepatic metastasis following surgical resection and transplantation. However, the intricate tumor microenvironment and transcriptional programs underlying MVI in HCC remain poorly understood. Approach and Results: We performed single-cell RNA sequencing of 46,789 individual cells from 10 samples of MVI+ (MVI present) and MVI- (MVI absent) patients with HCC. We conducted comprehensive and comparative analyses to characterize cellular and molecular features associated with MVI and validated key findings using external bulk, single-cell, and spatial transcriptomic datasets coupled with multiplex immunofluorescence assays. The comparison identified specific subtypes of immune and stromal cells critical to the formation of the immunosuppressive and pro-metastatic microenvironment in MVI+ tumors, including cycling T cells, lysosomal associated membrane protein 3+ dendritic cells, triggering receptor expressed on myeloid cells 2+ macrophages, myofibroblasts, and arterial i endothelial cells. MVI+ malignant cells are characterized by high proliferation rates, whereas MVI- malignant cells exhibit an inflammatory milieu. Additionally, we identified the midkine-dominated interaction between triggering receptor expressed on myeloid cells 2+ macrophages and malignant cells as a contributor to MVI formation and tumor progression. Notably, we unveiled a spatially co-located multicellular community exerting a dominant role in shaping the immunosuppressive microenvironment of MVI and correlating with unfavorable prognosis. Conclusions: This study provides a comprehensive single-cell atlas of MVI in HCC, shedding light on the complex multicellular ecosystem and molecular features associated with MVI. These findings deepen our understanding of the underlying mechanisms driving MVI and provide valuable insights for improving clinical diagnosis and developing more effective treatment strategies.
Letter to the Editor: Lack of complete biochemical response in autoimmune hepatitis leads to adverse outcome—First report of the IAIHG retrospective registry
Authors: Shubei He, Ying Peng, Qinglin Wei
Journal: Hepatology (2023)

1Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, China 2Department of Gastroenterology, Seventh Medical Center of PLA General Hospital, Beijing, China 3Department of Cadre Diagnosis and Treatment, Seventh Medical Center of PLA General Hospital, Beijing, China Correspondence Qinglin Wei, Department of Gastroenterology, Seventh Medical Center of PLA General Hospital, Beijing, China. E-mail: [email protected]
Reply: Lack of complete biochemical response in autoimmune hepatitis leads to adverse outcome—First report of the IAIHG retrospective registry
Authors: Charlotte D. Slooter, Floris F. van den Brand, Ana Lleo, Rodrigo Liberal, Ynto S. de Boer
Journal: Hepatology (2023)

Slooter, Charlotte D.; van den Brand, Floris F.; Lleo, Anna; Liberal, Rodrigo; de Boer, Ynto S. Author Information
Immunogenomics of cholangiocarcinoma
Authors: Virag Gehl, Colm J. O’Rourke, Jesper B. Andersen
Journal: Hepatology (2023)

The development of cholangiocarcinoma spans years, if not decades, during which the immune system becomes corrupted and permissive to primary tumor development and metastasis. This involves subversion of local immunity at tumor sites, as well as systemic immunity and the wider host response. While immune dysfunction is a hallmark of all cholangiocarcinoma, the specific steps of the cancer-immunity cycle that are perturbed differ between patients. Heterogeneous immune functionality impacts the evolutionary development, pathobiological behavior, and therapeutic response of these tumors. Integrative genomic analyses of thousands of primary tumors have supported a biological rationale for immune-based stratification of patients, encompassing immune cell composition and functionality. However, discerning immune alterations responsible for promoting tumor initiation, maintenance, and progression from those present as bystander events remains challenging. Functionally uncoupling the tumor-promoting or tumor-suppressing roles of immune profiles will be critical for identifying new immunomodulatory treatment strategies and associated biomarkers for patient stratification. This review will discuss the immunogenomics of cholangiocarcinoma, including the impact of genomic alterations on immune functionality, subversion of the cancer-immunity cycle, as well as clinical implications for existing and novel treatment strategies.